The Impact of Fear and Anxiety on the Human Immune System: Part II

December 14, 2021

“When the people fear the government, that’s tyranny; when the government fears the people, that’s freedom”.

A spurious quote commonly misattributed to Thomas Jefferson (1).

As described previously in, ‘The Impact of Fear and Anxiety on the Human Immune System: Part I’, fear has detrimental effects on our innate immunity. Here I continue to describe naturopathic treatment principles and naturopathic treatments including dietary, lifestyle and herbal medicine and nutritional supplement recommendations to reprogramme the innate immune system to produce immunological memory, whilst also addressing the pandemic of fear. 

Naturopathic Treatment Principles

Alarm and resistance stage: activate the parasympathetic nervous system, lower cortisol and tonify the nervous system

During the Alarm and the Resistance stage, the naturopathic treatment principles are to activate the parasympathetic nervous system and to lower stress hormones using nervous system herbal medicines. From a biomedical perspective, the exhaustion stage is usually referred to as adrenal insufficiency and thought of as Addison's disease. Naturopaths however, treat adrenal insufficiency or adrenal exhaustion. Vitamins and minerals are precursors to the production of stress hormones. Naturopathic philosophy supports the adrenal fatigue theory which suggests that prolonged exposure to stress, combined with nutritional deficiencies, leads to low adrenal hormone levels. The naturopathic treatment principle is to tonify the nervous system tonics (more so during the alarm phase) and tonify the adrenal glands using adaptogenic herbal medicines (more so in the latter stage).

Exhaustion stage: tonify the adrenal glands

The naturopathic treatment principle is to prescribe adaptogenic herbal medicines known as adaptogens. Adaptogens have an amphoteric action on the adrenal gland, meaning they can increase cortisol levels in cases of deficiency, and reduce adrenal hormones in cases of excess. Adaptogens are pleiotropic by nature, meaning they exhibit actions that are unrelated to the primary action of the herbal medicine, thus herbal medicine can target the neuroendocrine-immune system. Adaptogens are traditionally used as antiaging herbal medicines and to promote health and vitality. Adaptogens exhibit what scientists call a biphasic dose-effect response. In naturopathy, we call describe this as having an amphoteric effect. At low doses, adaptogens function as mild stress-mimetics, to act as challengers and mild stressors. This activates the adaptive stress-response signalling pathways which play an important role in the maintenance of homeostasis which helps us adapt to chronic stress. The traditional concept of adaptogens is evolving into medical systems for the treatment of stress-related and age-related disease (2). Adaptogens with angiotensin-converting enzyme 2 (ACE2) inhibitory effects have the added potential benefit to promote balance between pro- and anti-inflammatory immune responses to stress. Moreover, a meta-analysis of randomised clinical trials concluded that blockade of the angiotensin system improves mental health and quality of life (3). I provide examples of herbal adaptogens and ACE inhibitors further down under ‘Herbal Medicine’.

Encourage trained immunity

Naturopathic treatment principles are also centralised around boosting natural immunity. Scientists have recently termed this boosting of natural immunity as ‘innate immune training’ or ‘trained immunity’. Trained immunity involves epigenetic (behavioural and environmental risk factors) and metabolic reprogramming of the innate immune cells. Such training is directly relevant to resistance against infectious diseases, including COVID-19 (4). The following advice addresses these specific epigenetic and metabolic causes, to assist in this reprogramming of or innate immunity to achieve immunological memory. Again, long‐term reprogramming of the innate immune system to produce immunologically memory is a promising new discovery, as immunological memory is normally only associated with adaptive immunity. 

Naturopathic Treatment Principles to Calm Fear and Train Innate Immunity

Eat a whole foods diet

Consistent epidemiological evidence exists linking diet and mental and general health. High intake of highly refined carbohydrates, sugar, saturated and trans-fatty acids is associated with depression and anxiety, whereas a whole foods diet rich in vegetables, fruit, pulses (legumes), seeds, nuts and fish, is inversely associated with the risk of depression and anxiety (5, 6). Processed diets low in antioxidants, fibre, and polyunsaturated fatty acids (PUFAs), such as omega-3 fatty acids (ω−3 fatty acids/ n−3 fatty acids), may cause an activation of the innate immune system via excessive production of proinflammatory cytokines and associated reduction in the production of anti-inflammatory cytokines. The Mediterranean Diet is based on the traditional cuisines of France, Italy, Greece and other countries bordering the Mediterranean Sea. The antiinflammatory and immune protective effects of the Mediterranean diet high in PUFAs are well documented. This dietary pattern is characterised by the abundant consumption of olive oil, high consumption of plant foods including fruits, vegetables, grains and legumes, cereals, nuts and seeds, frequent and moderate intake of wine (the French Paradox), moderate consumption of seafood, yoghurt, cheese, poultry and eggs,  and low consumption of red meat and processed meats (7). 

Flatten insulin levels

High-glycaemic-index (GI) diets increase cortisol levels (8). High-GI foods also increase inflammation in the body and suppress immunity. High-GI foods such as sugar and refined grains, which are common ingredients in ultra-processed foods, increase oxidative stress. This activates inflammatory genes which leads to a state of chronic inflammation that suppresses immunity. Low-GI foods result in lower but more sustained increases in blood glucose and lower insulin demands on pancreatic β-cells (5). The aforementioned Mediterranean diet is in essence a low-GI diet.

Avoid excess stimulants

Both alcohol and coffee are immunomodulatory. Small doses promote the immune system, whilst excess doses suppress immune response. Excess alcohol negatively affects host immunity by promoting proinflammatory immune responses. Alcohol also impairs anti-inflammatory cytokines (9). A number of in vitro and in vivo studies have demonstrated that caffeine modulates both innate and adaptive immune responses (10).

Lifestyle Advice

Restful sleep

The connection between adequate sleep and immune function has long been established. Sleep and the circadian system exert a strong regulatory influence on immune function.  Sleep deprivation increases inflammation and suppresses the immune system. Studies have revealed a selectively enhancing influence of restful sleep on cytokines promoting the interaction between antigen-presenting cells and T helper cells (11). Achieving sufficient and regular undisturbed sleep can counteract the development of harmful stress and enhance antiviral immune defences. For decades, studies have linked sleep deprivation to decreases NK cell activity. The positive news is that after a night of resumed nocturnal sleep, NK cell activity returns to normal (12).

Get active

Getting active increases NK-cell activity and upregulates the immune-protective angiotensin 1-7. In contrast, more intense sportive activity can suppress innate immunity. Exercise stress can mobilise innate immune-defence cells such as NK cells, non-classical monocytes and differentiated subsets of CD8+ T-cells (5). My favourite outdoor activities are gardening and cycling which are free.

Tai chi and qigong and yoga

A systematic review and meta-analysis of the effects of Tai Chi and Qigong on immune responses found that these practices lower inflammatory markers and strengthen immune response (13). Studies have shown that yoga lowers cortisol levels, increases resilience and pain tolerance, and improves mood and reduces anxiety. Yoga reduces evening cortisol, as well as waking cortisol, systolic blood pressure, heart rate, heart-rate variability, fasting blood glucose, cholesterol and low-density lipoprotein  (14). Mindfulness is basic concentration training derived from Buddhism.Mindfulness is simply having an awareness of the present moment, which provides an opportunity to acknowledge and accept difficult physical and emotional sensations, and to help calm and focus the mind. Mindfulness is also free.

Progressive muscle relaxation

Progressive muscle relaxation (PMR) involves intentionally tensing and releasing various muscles groups while you breathe in or out, to relieve tension, and calm and focus the mind. Brain wave samples with dominant frequencies belonging to beta, alpha, theta, and delta bands and gamma waves. During non-REM sleep, the slower, lower-frequency theta and delta waves dominate (15). Progressive muscle relaxation consciously trains the brain to relax. PMR has been shown to reduce anxiety and improve sleep in isolated COVID-19 patients (5). Again, it is absolutely free.

Surround yourself in nature

Spending time in nature is by far the easiest way for many people to unwind and relax. The traditional Japanese practise of shinrin-yoku, literally meaning forest bathing, combines walking in a forest, observing it, and breathing in the scents to stimulate the senses and calm and focus the mind. The Japanese use this as a kind of meditation. A systematic review and meta-analysis of shinrin-yoku confirmed its cortisol-decreasing potential. Forest bathing may reduce pulse rate, fatigue, anxiety and depression, and increase vigour (5).

Socialise and laugh

The mental and physical health benefits that socialising are well recognised. In Ireland we say, to have the ‘craic’. There is evidence that laughter and good humour can reduce stress and pain, and improve healing. (16) Additionally, laughter is reported to influence the immune system and increase NK cell activity (17). Social distancing is not only antisocial, it increases susceptibility to SARS-CoV-2 infection, and increases the risk of severe COVID-19 disease.  

Herbal Medicine

Adaptogenic herbal medicines

There are a plethora of adaptogenic herbal medicines that are suitable in the 21st century to treat this pandemic of fear. A wide crossover between Eastern and Western herbal medicines exist, however many of the adaptogenic herbal medicines are known to derive from the Traditional Chinese and Ayurvedic medicine systems. There are primary and secondary adaptogens. Primary adaptogens have a direct effect on the HPA axis. Primary adaptogens can also both maintain or recover homeostasis and allostasis (adaption to maintain homeostasis), and promote anabolic recovery. Studies have confirmed that the following plants are true primary adaptogens: Chinese ginseng (Panax ginseng), Schisandra (Schisandra chinensis), Siberian ginseng (Eleutherococcus senticosus), Rhodiola (Rhodiola crenulata), Peruvian ginseng / maca (Lepidium meyenii) and Withania / Indian ginseng  (Withania somnifera). Another category of adaptogens is secondary adaptogens, which are consistent with most traditional definitions of adaptogens but do not affect the HPA axis. These adaptogens affect the immune, nervous and endocrine systems. Echinacea (Echinacea purpurea) and (Echinacea angustifolia) are both immune stimulant and adaptogenic (18, 19). Nervous system tonic herbal medicines such as German chamomile (Matricaria recutita), lemon balm (Melissa officinalis) and oat straw (Avena sativa) are indicated. Traditionally speaking, oat seeds are more stimulating, whilst the leaves and stem are said to be more calming.

Natural ace inhibitors

As previously mentioned in, 'The Impact of Fear and Anxiety on the Human Immune System: Part I'. ACE II levels are associated with hyperinflammatory states, and it is assumed that elevated levels of ACE II could aggravate the course of COVID-19 infection. A comparative study investigating the antioxidant properties and phenolic contents (total phenols, flavonoids, flavonols and proanthrocyanidins), and ACE inhibitory activities of selected herbal extracts, found that Indian gooseberry (Phyllanthus emblica) has the strongest ACE inhibition potential followed by, withania (Withania somnifera), roselle (Hibiscus sabdriffa), ginkgo (Ginkgo biloba), tulsi  (Ocimum sanctum) and garlic (Allium sativum) (20). Additionally, there is an added benefit; a meta-analysis of randomised clinical trials concluded that a blockade of the angiotensin system improves mental health and quality of life (3).

Anti-inflammatory herbal medicines

Suppression of the cytokine release correlates with reduced death rates in clinical diseases such as pandemic influenza, where a cytokine storm plays a significant role in high mortality rates (21). Many natural immunosuppressant herbal medicines exist as potential adjuvants to target the cytokine storm in COVID-19. Several plants and plant-derived bioactive compounds have been studied for their immunomodulatory activity, and many have been identified for their immunosuppressive activity in particular (22). The immune-modulatory activities of echinacea (Echinacea purpurea) comprise stimulation of macrophage phagocytic activity and suppression of the proinflammatory cytokines and chemokine responses of epithelial cells to viruses and bacteria (23). The active constituent andrographolide in andrographis (Andrographis paniculata) inhibits influenza A virus and reduces inflammatory cytokine expression induced by infection (24). Turmeric (Curcuma longa) inhibits key proinflammatory cytokines, interleukin (IL) IL-1, IL-6 and tumour necrosis factor (TNF) TNF-α (25).  

Nutritional Supplements

As previously mentioned in ‘The Impact of Fear and Anxiety on the Human Immune System: Part I’, oxidative stress can cause chronic inflammation. Antioxidants directly or indirectly scavenge reactive oxygen species (ROS). Naturopaths often work to increase our endogenous antioxidant ROS scavengers; catalase, glutathione peroxidase (GPx), glutathione-s-transferase (GST), and superoxide dismutase (SOD). Nutritional supplements or neutraceuticals essential for the proper functioning of the immune system are indicated. These include omega-3 polyunsaturated fatty acids(ω−3-PUFAs), N-acetylcysteine, S-adenosylmethionine, vitamin B and D, and selenium. Selenium deficiency not only weakens the immune response against viruses but may even increase the virulence of viruses by causing mutations in the viral genome, likely due to increased oxidative stress in the host cells (5). Selenium-dependent antioxidant enzymes include catalase, GPx and SOD (26). The main nutritional precursors to endogenous antioxidants include vitamin C, and vitamin E, which is widely accepted as the most potent radical-scavenging lipophilic antioxidant (27). 

Worth noting here, and warranting further discussion in future articles on VSS, a variety of herbal medicines ‘spare’ our endogenous antioxidant free radical scavengers. For example, silymarin in milk thistle (Silybum marianum) and berberine containing herbal medicines such as in barberry (Berberis vulgaris), increase GPx and SOD (28, 29). 

Pre- and probiotics

Immune system stimulation by pre- and probiotics microorganisms is well established.  Pre- and probiotics stimulate the immune system, by increasing the expression of anti-inflammatory cytokines, while reducing the expressions of proinflammatory cytokines (30). I recommend Kefir and kombucha. My Irish grandmother drank buttermilk. Most cultures have a fermented milk product. There are many supplements available.

Conclusion

‍As explained in a video entitled, ‘Billions Of People Are Affected By This and They Don't Realise It’, inventor of the mRNA vaccine Dr. Robert Malonedescribes psychologist and statistician from Ghent University, Belgium Mattais Desmet’s theory as to how we got here, what we can expect, and where we go from here. Malone describes Desmet’s theory of mass formation psychosis, mass as in crowd. The precursors to this mass hysteria are a lack of human connection. The hypnosis we are experiencing is being formed by our obsession over one thing. This fundamental phenomenon of the human mind creates a mass formation psychoses. This is what happened in Germany, and is happening in Germany again. The crowd can see, hear or speak no evil and anyone who says anything outside narrative must be denigrated and vilified. Some of us are impervious to propaganda, through life experiences.  Desmet explains we must substitute the fear of the virus with a greater threat, which is the fear of global totalitarian control. That, and the other two things very close to my heart,  society as a whole must get healthy and break our dependence on public health, and  I think angry Moms may be the thing that saves our democracy (31). All of the public health advice currently recommended, bar washing your hands with soap and water, weakens our innate immunity and makes us more susceptible to all diseases, including COVID-19. Treat your body like a temple and trust your gut. 

‍

Abbreviations

- Angiotensin-converting enzyme 2 (ACE2)

- Glycaemic-index (GI)

- Healthcare workers (HCWs)

- Hypothalamus-pituitary-adrenal (HPA)

- Interferons (IFNs)

- Interleukin-1β (IL-1β)

- Major histocompatibility complex (MHC)

- MHC class 1 (MHC I) and MHC class 2 (MHC II)

- Natural Killer (NK) cell

- Nuclear factor-kappa B (NF-κB)

- Omega-3 fatty acids (ω−3 fatty acids/ n−3 fatty acids)

- Progressive muscle relaxation (PMR)

- Reactive oxygen species (ROS)

- Severe acute respiratory syndrome CoV 2 (SARS-CoV-2)

- Tumour necrosis factor-alpha (TNF-α) 

‍

References:

1. Monticello. When government fears the people, there is liberty... (Spurious Quotation) [Internet]. Charlottesville, VA Monticello and the Thomas Jefferson Foundation; 2020 [Available from: https://www.monticello.org/site/research-and-collections/spurious-quotations.]

2. Panossian AG, Efferth T, Shikov AN, Pozharitskaya ON, Kuchta K, Mukherjee PK, et al. Evolution of the adaptogenic concept from traditional use to medical systems: Pharmacology of stress- and aging-related diseases. Medicinal research reviews. 2021;41(1):630-703.

3. Brownstein DJ, Salagre E, Köhler C, Stubbs B, Vian J, Pereira C, et al. Blockade of the angiotensin system improves mental health domain of quality of life: A meta-analysis of randomized clinical trials. Australian & New Zealand Journal of Psychiatry. 2018;52(1):24-38.

4. Mantovani A, Netea MG. Trained Innate Immunity, Epigenetics, and Covid-19. New England Journal of Medicine. 2020;383(11):1078-80.

5. Peters EMJ, Schedlowski M, Watzl C, Gimsa U. To stress or not to stress: Brain-behavior-immune interaction may weaken or promote the immune response to SARS-CoV-2. Neurobiol Stress. 2021;14:100296.

6. Adan RAH, van der Beek EM, Buitelaar JK, Cryan JF, Hebebrand J, Higgs S, et al. Nutritional psychiatry: Towards improving mental health by what you eat. Eur Neuropsychopharmacol. 2019;29(12):1321-32.

7. Casas R, Sacanella E, Estruch R. The immune protective effect of the Mediterranean diet against chronic low-grade inflammatory diseases. Endocr Metab Immune Disord Drug Targets. 2014;14(4):245-54.

8. Al-Dujaili EAS, Ashmore S, Tsang C. A Short Study Exploring the Effect of the Glycaemic Index of the Diet on Energy intake and Salivary Steroid Hormones. Nutrients. 2019;11(2).

9. Szabo G, Saha B. Alcohol's Effect on Host Defense. Alcohol Res. 2015;37(2):159-70.

10. Horrigan LA, Kelly JP, Connor TJ. Immunomodulatory effects of caffeine: friend or foe? Pharmacol Ther. 2006;111(3):877-92.

11. Besedovsky L, Lange T, Born J. Sleep and immune function. Pflugers Arch. 2012;463(1):121-37.

12. Irwin M, Mascovich A, Gillin JC, Willoughby R, Pike J, Smith TL. Partial sleep deprivation reduces natural killer cell activity in humans. Psychosom Med. 1994;56(6):493-8.

13. Oh B, Bae K, Lamoury G, Eade T, Boyle F, Corless B, et al. The Effects of Tai Chi and Qigong on Immune Responses: A Systematic Review and Meta-Analysis. Medicines (Basel). 2020;7(7).

14. Katuri KK, Dasari AB, Kurapati S, Vinnakota NR, Bollepalli AC, Dhulipalla R. Association of yoga practice and serum cortisol levels in chronic periodontitis patients with stress-related anxiety and depression. J Int Soc Prev Community Dent. 2016;6(1):7-14.

15. Başar E, Başar-Eroğlu C, Güntekin B, Yener GG. Brain's alpha, beta, gamma, delta, and theta oscillations in neuropsychiatric diseases: proposal for biomarker strategies. Suppl Clin Neurophysiol. 2013;62:19-54.

16. Hayashi K, Kawachi I, Ohira T, Kondo K, Shirai K, Kondo N. Laughter is the Best Medicine? A Cross-Sectional Study of Cardiovascular Disease Among Older Japanese Adults. Journal of epidemiology. 2016;26(10):546-52.

17. Yoshikawa Y, Ohmaki E, Kawahata H, Maekawa Y, Ogihara T, Morishita R, et al. Beneficial effect of laughter therapy on physiological and psychological function in elders. Nurs Open. 2019;6(1):93-9.

18. Liao LY, He YF, Li L, Meng H, Dong YM, Yi F, et al. A preliminary review of studies on adaptogens: comparison of their bioactivity in TCM with that of ginseng-like herbs used worldwide. Chin Med. 2018;13:57.

19. Megna M, Amico AP, Cristella G, Saggini R, Jirillo E, Ranieri M. Effects of herbal supplements on the immune system in relation to exercise. Int J Immunopathol Pharmacol. 2012;25(1 Suppl):43s-9s.

20. Chaudhary N, Sabikhi L, Hussain SA, Kumar M H S. A comparative study of the antioxidant and ACE inhibitory activities of selected herbal extracts. Journal of Herbal Medicine. 2020;22:100343.

21. Tang Y, Liu J, Zhang D, Xu Z, Ji J, Wen C. Cytokine Storm in COVID-19: The Current Evidence and Treatment Strategies. Frontiers in immunology. 2020;11:1708-.

22. Peter AE, Sandeep BV, Rao BG, Kalpana VL. Calming the Storm: Natural Immunosuppressants as Adjuvants to Target the Cytokine Storm in COVID-19. Frontiers in Pharmacology. 2021;11(2305).

23. Aida Sivro DRS, Lyle R. McKinnon. The Role of Cytokine Storm in Influenza Pathogenesis. Purple Paper. 2011(23).

24. Ding Y, Chen L, Wu W, Yang J, Yang Z, Liu S. Andrographolide inhibits influenza A virus-induced inflammation in a murine model through NF-kappaB and JAK-STAT signaling pathway. Microbes and infection. 2017;19(12):605-15.

25. Sordillo PP, Helson L. Curcumin suppression of cytokine release and cytokine storm. A potential therapy for patients with Ebola and other severe viral infections. In vivo (Athens, Greece). 2015;29(1):1-4.

26. Zoidis E, Seremelis I, Kontopoulos N, Danezis GP. Selenium-Dependent Antioxidant Enzymes: Actions and Properties of Selenoproteins. Antioxidants (Basel). 2018;7(5).

27. Lobo V, Patil A, Phatak A, Chandra N. Free radicals, antioxidants and functional foods: Impact on human health. Pharmacogn Rev. 2010;4(8):118-26.

28. Kim YC, Na JD, Kwon DY, Park JH. Silymarin prevents acetaminophen-induced hepatotoxicity via up-regulation of the glutathione conjugation capacity in mice. Journal of Functional Foods. 2018;49:235-40.

29. Lao-ong T, Chatuphonprasert W, Nemoto N, Jarukamjorn K. Alteration of hepatic glutathione peroxidase and superoxide dismutase expression in streptozotocin-induced diabetic mice by berberine. Pharmaceutical biology. 2012;50(8):1007-12.

30. Shokryazdan P, Faseleh Jahromi M, Navidshad B, Liang JB. Effects of prebiotics on immune system and cytokine expression. Med Microbiol Immunol. 2017;206(1):1-9.

31. Malone Dr., Billions Of People Are Affected By This & They Don't Realize It | In: Inspired, editor.: YouTube; 2021.